Diabetes mellitus is one of the common systemic diseases affecting the kidneys, often resulting in diabetic nephropathy. In fact, diabetic nephropathy will likely develop in a third of those patients who have had type 1 diabetes for more than 20 years. Diabetic nephropathy typically affects the network of tiny blood vessels (the microvasculature) in the glomerulus, a key structure in the kidney composed of capillary blood vessels. The glomerulus is critically necessary for the filtration of the blood. Features of diabetic nephropathy include the nephrotic syndrome with excessive filtration of protein into the urine (proteinuria), high blood pressure (hypertension), and progressively impaired kidney function. When it is severe, diabetic nephropathy leads to kidney failure, end-stage renal disease, and the need for chronic dialysis or a kidney transplant.
The involvement of diabetes in diabetic nephropathy is essentially glomerular. The primary pathogenic role of hyperglycemia in diabetic renal disease is so well established that diabetic nephropathy is today considered as hyperglycemic glomerulopathy. Mortality and morbidity in these patients is often due to cardiovascular disease, probably accelerated by hypertension and hyperlipidemia. Biochemical, hormonal, immunological and rheological factors have been shown to be etiologically important in the pathogenesis of diabetic nephropathy. The biochemical factors implicated include hyperglycemia and glycosylated proteins in blood and basement membrane of the kidneys. Also, there is experimental and clinical evidence to suggesting that recruitment of monocytes into glomeruli may play a role in the pathogenesis of this diabetic complication.
Diabetes mellitus accounts for about one-third of all end-stage renal disease. The landmark study by Lewis et. al. 1993 demonstrates that, in patients with type 1 diabetes mellitus and diabetic nephropathy, Captopril prevents or delays the progression of renal disease. These findings are have been generalized to other Angiotensin Converting Enzyme inhibitors (ACE inhibitors) and to patients with both type 1 and type 2 diabetes regardless of baseline renal function or arterial blood pressure (Ravid et. al. 1993, 1996). In addition to preventing diabetic nephropathy, ACE inhibitors also may decrease retinopathy progression in type 1 diabetics (Chaturvedi et. al. 1998).
Several mechanisms participate in the renal protection afforded by ACE inhibitors. Increased glomerular capillary pressure induces glomerular injury, and ACE inhibitors reduce this parameter both by decreasing arterial blood pressure and by dilating renal efferent arterioles. Because angiotensin II is a growth factor, reductions in the intrarenal levels of angiotensin II may further attenuate mesangial cell growth and matrix production.
Mycophenolate mofetil (MMF) is prodrug that is rapidly hydrolyzed to mycophenolic acid (MPA), a selective, uncompetitive, and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of guanine nucleotide synthesis. B and T lymphocytes are highly dependent on this pathway for cell proliferation, while other cell types can use salvage pathways. MPA therefore selectively inhibits lymphocyte proliferation and functions, including antibody formation, cellular adhesion, and migration. The effects of MPA on lymphocytes can be reversed by adding guanosine or deoxyguanosine to the cells (Krensky et. al. 2001).
MMF ameliorates the renal lesions in several models of experimental glomerular disease. The ability of MMF to suppress not only the immune response, but also smooth cell proliferation, makes the drug a candidate for preventing renal fibrosis. This is because myofibrobalsts share many features with vascular smooth muscle cells. Preliminary results suggest that MMF is effective in several types of glomerulonephritis after conventional therapy had failed (Badid et. al. 2001).
Two recent studies have evaluated the impact of MMF in patients with IgA nephropathy. Preliminary results from both of these studies were presented at the 2001 Annual Meeting of the American Society of Nephrology (Chen et. al. 2001 and Maes et. al. 2001). Chen et al, from China, compared the effect of MMF Vs Prednisone in 62 patients. The age of these patients ranged from 9-54 years and each of the patients had protein excretion rates >2g per day. The dose of the MMF given to the patients varied from 1-1.5g per day whereas a control group received 30-40 mg of Prednisone per day. Fifteen patients in each of the groups had been followed for seventy two weeks. Whereas both groups of patients showed reduction of proteinuria after 3 and 6 months, the decrease in the MMF patients was greater after 6 months. This decrease in proteinuria continued in the MMF group through 72 weeks. Chen, et al concluded in this preliminary report that MMF was superior to Prednisone in decreasing proteinuria, protecting renal function and also decreasing blood lipid levels.
With most immunosuppressive agents, increasing the degree of immunosuppression increases the likelihood of side effects of immunosuppression, including infection and bone marrow suppression. However, experience from controlled clinical trials in renal transplantation shows that MMF may be an exception to this generalization because the MMF-treated patients were able to achieve a greater degree of immunosuppression yet suffered little increase in the incidence of infection or bone marrow suppression (Dooley et. al. 1999).
Dooley and his coworkers concluded in their study that MMF is well tolerated and has possible efficacy in controlling major renal manifestation of systemic lupus erythomatosis. In lupus nephritis, these authors found that 0.5 to 1.5 g/d dose of MMF were sufficient. Miller et. al. 2000 in their study of mycophenolate mofetil use in resistant membranous nephropathy, used 0.5 to 2.0 g/d dose of MMF. The dose of MMF was titrated according to leukocyte counts and side effects, in most cases because of gastrointestinal symptoms.
The most obvious endpoint for treatment failure in patients with diabetic nephropathy is progression to end stage renal disease (ESRD). However, since the period from diagnosis to ESRD in diabetic nephropathy patients with normal renal function at onset may be over 10 years. Only about 30% of diabetics live for 10 years beyond the onset of clinical proteinuria. The degree of diabetes control is a necessary component, but is not linearly related to the development of renal failure. Control of hyperglycemia may become very difficult in nephropathic diabetic. Normalizing the blood pressure at every stage of progressive diabetic renal disease is stressed as an important component of the therapeutic program. Apart from the control of systemic hypertension, control of intraglomerular hypertension is also considered important in diabetic nephropathy. ACE inhibitors have been shown to lower the intraglomerular hypertension and thus reduce hyperfiltration of diabetic nephropathy. It is therefore, recommended that in diabetics with even normal blood pressure, ACE inhibitors be given to lower intraglomerular pressure.
It was reported that mycophenolate mofetil prevents the development of glomerular injury in experimental diabetes (Utimura et. al. 2003). Diabetic rats exhibited marked glomerular hyperfiltration and hypertension. They developed progressive albuminuria and exhibited widespread glomerulosclerotic lesions associated with macrophage infiltration at 8 months. Treatment with MMF had no effect on blood pressure, glomerular dynamics or blood glucose levels, but did prevent albuminuria, glomerular macrophage infiltration and glomerulosclerosis.
In light of the above, there remains an unmet need for therapies for treating diabetic nephropathy and its related symptoms.